When the completion of the rough draft sequence of the human genome was announced in 2000, it represented a major advance in genetics. It ushered in new information about our genes and promised real progress toward personalized medicine.

But the Human Genome Project was time-consuming and costly—it began in 1990, was formally completed in 2003, and cost $2.7 billion. Of course, since then, deciphering the DNA sequence of individual genomes has seen significant progress. “There has been a large shift in the last several years for methods of DNA sequencing,” explained Jay Shendure (pictured below), a University of Washington geneticist who in concert with a team of researchers in Seattle is working on a project aimed at streamlining genomic sequencing technologies.

Shendure and Sarah Ng, a UW graduate student supported by A*STAR (the Agency for Science, Technology and Research) in Singapore, are involved in the Exome Project, an effort funded by the National Institutes of Health that is focused on developing cost-effective, rapid methods for sequencing parts of the human genome known as exons. Exons are the segments of DNA that produce proteins—the building blocks of the human body.

“Our angle was to focus our resources on the 1 percent (the exons) of the human genome that codes for proteins,” Shendure said. That’s not to say that the other 99 percent, much of which has been referred to as “junk” DNA because it was believed to serve no function, is unimportant. In fact, scientists are discovering that these non-protein-encoding regions may actually play vital roles in regulating the activity of those genes that do produce proteins. But the exons, as Shendure pointed out, “may be the 1 percent that matters most.”

In their study, which was released in an August 2009 advanced online publication of Nature (due in print Sept. 10), Shendure, Ng, and their collaborators used exome sequencing technology to detect causative gene mutations of a rare disease known as Freeman-Sheldon syndrome, or FSS. FSS is characterized by deformed and contracted joints and other skeletal malformations. To identify the genes that cause the disease, the team optimized an already existing method for capturing exons.

They first chopped up DNA that had been isolated from cells of both healthy individuals and patients with FSS. They then “pulled out” the exons, separating them from introns and other bits of DNA, using microarray technology. The microarrays contained short segments of DNA that were complementary to exon sequences, resulting in exon-microarray binding and thereby isolating the exons from the rest of the genome. The isolated exons were then sequenced, and in this way the researchers successfully identified DNA differences (single nucleotide polymorphisms) in the “exomes” of 12 people. By looking for polymorphisms that were present in the individuals with FSS, but not in the healthy individuals, they were able to identify the causative gene underlying the syndrome.

The major impetus of the study was proving that exome sequencing could be affordable and effective. Shendure explained that the cost of sequencing the human genome has dropped in the last few years, from prohibitive billions to a mere $50,000 per genome. But this still is too expensive, both for purposes of basic research and for applications in clinical medicine, which is why narrowing in on the small fraction of the genome with known functions is so appealing.

For university-based labs, Shendure and Ng’s exome approach is far more practical than existing methods of genome sequencing for the detection of rare diseases. “The sequencing and associated technologies are at the stage where a graduate student in a small lab like ours can take on a project of this scale,” Ng said. “Just a couple of years ago it would have required the resources of a genome center.”

Shendure and Ng indicated that the most significant impact of their work, at least for now, remains in the realm of basic research, though they hope that this won’t be the case for very long. “Genomics is not used that much in the clinic [right now],” Shendure explained. “But exome sequencing could have a niche in the detection of rare, highly penetrant phenotypes.” In other words, exome sequencing might eventually be used to confirm the diagnosis of any one of the several thousands of rare disorders that are caused by defects in single genes.

According to Ng, this is just the beginning. “We’re happy with how it has turned out so far,” she said. “In the immediate future we’ll be using this approach to find the causal genes for more rare diseases and syndromes. Finding these genes will not only be informative about the disease but will give us insight into how they contribute to normal development and function.”